The transmembrane protein carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, also known as biliary glycoprotein (BGP), CD66a and C-CAM1), is a member of the carcinoembryonic antigen family (CEA) that also belongs to the immunoglobulin superfamily. Human CEACAM1 has been assigned the SwissProt accession number P13688. CEACAM1 interacts with itself and with other known CEACAM proteins, including CD66e (CEACAM6) and CD66e (CEACAM5, CEA) proteins. It is expressed on a wide spectrum of cells, ranging from epithelial cells to those of hemopoietic origin (e.g. immune cells).
Many different functions have been attributed to the CEACAM1 protein. It was shown that the CEACAM1 protein is over expressed in some carcinomas of colon, prostate, as well as other types of cancer, such as melanoma. Additional data support the central involvement of CEACAM1 in angiogenesis and metastasis. CEACAM1 also plays a role in the modulation of innate and adaptive immune responses. For example, CEACAM1 was shown to be an inhibitory receptor for activated T cells contained within the human intestinal epithelium (WO 99/52552 and Morales et al. J. Immunol. 1999, 163, 1363-1370). Additional reports have indicated that CEACAM1 engagement either by T cell receptor cross-linking with monoclonal antibodies (mAbs) or by Neisseria gonorrhea Opa proteins inhibits T cell activation and proliferation. Several monoclonal antibodies against the CEACAM1 protein are already known, such as 26H7, 5F4, TEC-11, 12-140-4, 4/3/17, COL-4, F36-54, 34B1, YG-C28F2, D14HD11, b18.7.7, D11-ADM HEA81, B1.1, CLB-gran-10, F34-187, T84.1, B6.2, B1.13, YG-C94G7, 12-140-5, TET-2 and scFv-DIATHIS1 (Watt et al., Blood, 2001, Vol. 98, pages 1469-1479). WO 2010/12557 describes the murine a monoclonal antibody to human CEACAM1. WO 2013/054331 describes the chimeric a monoclonal antibody to human CEACAM1 CM10.
Programmed cell death protein 1 (PD-1) is a type I transmembrane protein belonging to the CD28/CTLA-4 family of immuno-receptors that mediate signals for regulating immune responses. Human PD-1 has been assigned the SwissProt accession number Q15116. Members of the CD28/CTLA-4 family either up-regulate (CD28 and ICOS) or down-regulate T cell activation (CTLA-4 and PD-1). PD-1 is expressed on activated T cells, B cells, myeloid cells and on a subset of thymocytes. Several monoclonal antibodies against the PD-1 protein are already known, such as MK-3475 (humanized IgG4 mAb), AMP514, BMS-936558 (fully human IgG4 mAb), and pidilizumab also known as CT-011 (humanized IgG1 mAb) (Topalian et al., Curr. Opin. Immunol., 2012, Vol. 24(2), pages 207-212).
Programmed cell death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene. PD-L1 is a 40 kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, and other disease states such as hepatitis. Normally, the immune system reacts to foreign antigens where there is some accumulation in the lymph nodes or spleen which triggers a proliferation of antigen-specific CD8+ T cell. The formation of PD-1/PD-L1 ligand complex transmits an inhibitory signal which reduces the proliferation of these CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene Bcl-2 (Chemnitz J M et al., 2004, Journal of Immunology, 173(2): 945-54). Engagement of PD-L1 with its receptor PD-1 found on activated T cells, B cells, and myeloid cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273 (cluster of differentiation 273).
PD-1 and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Human PD-L1 and PD-L2 have been assigned the SwissProt accession numbers Q9NZQ7 and Q9BQ51, respectively. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. Several monoclonal antibodies against the PD-L1 protein are already known, such as MEDI-4736, BMS-936559, MSB0010718C and MPDL3280A (Lu et al., J. Oncol. Pharm. Pract., 2014). Other monoclonal antibodies against the PD-L2 protein are also known, such as those disclosed in PCT application publication nos. WO/2010/027827, WO/2010/036959 and WO/2011/066342. WO/2014/059251 relates to compositions and methods for enhancing the immune response and/or reducing T cell tolerance in subjects by administering inhibitors of two or more of CEACAM1, PD-1 and/or latency associated peptide (LAP).
Cancer immunotherapy is the use of the immune system to treat cancer. There are three main groups of immunotherapy: cell-based therapies, antibody therapies and cytokine therapies. They all exploit the fact that cancer cells often have different molecules on their surface that can be detected by the immune system. These molecules are known as cancer antigens. Immunotherapy is used to provoke the immune system into attacking the tumor cells by using these cancer antigens as targets.
Antibody therapies are currently the most successful form of immunotherapy, with many approved treatments for a wide range of cancers. Antibodies are proteins produced by the immune system that bind to a target antigen on the surface of a cell. In normal physiology they are used by the immune system to fight pathogens. Each antibody is specific to one or few highly similar proteins and those that bind to cancer antigens are used in the treatment of cancer. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor interacting with its ligand or deliver a payload of chemotherapy or radiation, all of which can lead to cell death. There are antibodies currently approved for the treatment of cancer by the U.S. Food and drug administration (FDA): Rituximab (1997), Trastuzumab (1998), Gemtuzumab ozogamicin (2000), Alemtuzumab (2001), Ibritumomab tiuxetan (2002), Tositumomab (2003), Cetuximab (2004), Bevacizumab (2004), Panitumumab (2006), Ofatumumab (2009), Ipilimumab (2011) and Brentuximab vedotin (2011).
While originally approved as anti-cancer monotherapies, several antibodies were further approved for use in combination with other anti-cancer therapies, such as chemotherapy. For example, the FDA granted approval to Rituximab (Rituxan, Genentech, Inc.) in combination with fludarabine and cyclophosphamide for the treatment of both previously untreated and previously treated patients with chronic lymphocytic leukemia (CLL). Recently, the FDA approved Bevacizumab (Avastin, Genentech, Inc.) in combination with paclitaxel and either cisplatin or topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.
There remains an unmet need for improved combinatorial antibody-based therapies, employing a diversity of antibodies targeting distinct or parallel mechanisms of cancer progression.